Endothelin-1 Mediates Oxaliplatin Resistance via Activation of YAP Signaling in Colorectal Cancer

Colorectal cancer (CRC) is a predominant contributor to global cancer-associated mortality worldwide. Oxaliplatin (OXP), a foundational chemotherapeutic agent for CRC, often exhibits limited efficacy due to the emergence of drug resistance. Although endothelin-1 (EDN1) has been implicated in tumor drug resistance, its role in oxaliplatin resistance in CRC remains poorly defined. This work aimed to define how EDN1 contributes to oxaliplatin resistance and to explore its potential as a therapeutic target.

Public genomic datasets were analyzed to confirm EDN1 upregulation in colorectal cancer (CRC) and its association with poor prognosis. EDN1 expression was modulated in parental and oxaliplatin-resistant CRC cell lines via shRNA knockdown and lentiviral overexpression. Functional assays, including drug sensitivity, flow cytometry, and 5-Ethynyl-2^'-deoxyuridine (EdU) proliferation, were conducted to assess resistance. Mechanistic studies employed dual-luciferase reporter assays, Western blotting, co-immunoprecipitation, and immunofluorescence. CRC-derived subcutaneous xenograft models were used to evaluate the therapeutic efficacy of EDN1 targeting in vivo.

The study identifies EDN1 as a pivotal mediator of oxaliplatin resistance in CRC. EDN1 expression is markedly upregulated in oxaliplatin-resistant CRC cells and is significantly associated with poor patient survival outcomes. Mechanistically, EDN1 overexpression activates the Yes-associated protein (YAP) signaling by promoting the nuclear translocation of β-arrestin1 (β-arr1), thereby facilitating chemoresistance. Importantly, the combinatorial inhibition of EDN1, in conjunction with oxaliplatin treatment, substantially enhances apoptosis and suppresses tumor growth both in vitro and in vivo.

The study demonstrates that EDN1 governs oxaliplatin resistance through the β-arr1/YAP axis and provides preclinical evidence for targeting EDN1 to overcome chemoresistance in CRC.